The research will describe the neuroanatomical and neurochemical bases of ketamine's (Ketalar; Ketaject) analgesic effect. It will be accomplished by an evaluation of the presence and function of opiate receptor sub-types in neuroanatomical loci (i.e., sites known to be loci of morphine's analgesic action); a description of opiate receptor sub-types with which ketamine interacts; and a determination of the consequences of an interaction of ketamine at these receptors. The research is divided into five scientific approaches. Each is designed to provide component information important to the project as a whole and/or to test the same proposal under different conditions. The methods are: 1) a pharmacological comparison of the analgesic action in rats of various sub-classes of opiate drugs presumed to be specific for sub-types of opiate receptors, and an evaluation of the participation of monoaminergic and opiate neuronal processes in these analgesias; 2) an in vitro comparison of the receptor binding characteristics of ketamine and other opiate drugs, specific for different receptors, using opiate binding assays; 3) an in vivo evaluation of the ability of ketamine to interact with opiate receptors that may mediate its special pharmacological actions; 4) local administration of ketamine and opiate drugs, specific for different opiate receptors, into central nervous system loci (i.e., those sites responsible for morphine analgesia) and an analysis of the neurochemical and neuroanatomical bases for the resulting analgesia and 5)*an in vitro and in vivo analysis of the participation of opiate or non-opiate mechanism(s) in the spinal analgesic action of ketamine, a site of action of established differences between ketamine and morphine. The study should define ketamine's opiate receptor preference and action (agonistic-antagonistic) on various sub-types of receptors found in areas of the central nervous system associated with morphine's analgesic action. The possibility that ketamine uses neuronal circuitry activated by morphine is being tested. Ketamine may be found to be dissimilar to morphine and share components of analgesic mechanisms associated with other classes of opiate drugs. Differences in the analgesic mechanisms associated with various types of analgesic drugs will begin to be defined which is consistent with our long term goal to determine pathways and neurotransmitters of analgesia.*